This is not the most recent version of the article. View current version (7 NOV 2014)

Intervention Protocol

You have free access to this content

Pharmacological interventions for somatoform disorders in adults

  1. Maria Kleinstäuber1,*,
  2. Michael Witthöft2,
  3. Andrés Steffanowski3,
  4. Michael Lambert4,
  5. Günter Meinhardt5,
  6. Klaus Lieb6,
  7. Wolfgang Hiller2

Editorial Group: Cochrane Depression, Anxiety and Neurosis Group

Published Online: 4 JUL 2013

DOI: 10.1002/14651858.CD010628

How to Cite

Kleinstäuber M, Witthöft M, Steffanowski A, Lambert M, Meinhardt G, Lieb K, Hiller W. Pharmacological interventions for somatoform disorders in adults (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD010628. DOI: 10.1002/14651858.CD010628.

Author Information

  1. 1

    Philipps-University Marburg, Department of Clinical Psychology and Psychotherapy, Marburg, Hessen, Germany

  2. 2

    Johannes Gutenberg-University Mainz, Department of Clinical Psychology and Psychotherapy, Mainz, Rheinland-Pfalz, Germany

  3. 3

    University of Mannheim, Department of Psychology, Mannheim, Baden-Württemberg, Germany

  4. 4

    Brigham Young University, Department of Psychology, Provo, Utah, USA

  5. 5

    Johannes Gutenberg-University Mainz, Department of Methods in Psychology, Mainz, Rheinland-Pfalz, Germany

  6. 6

    University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz, Germany

*Maria Kleinstäuber, Department of Clinical Psychology and Psychotherapy, Philipps-University Marburg, Gutenbergstr. 18, Marburg, Hessen, D-35032, Germany.

Publication History

  1. Publication Status: New
  2. Published Online: 4 JUL 2013


This is not the most recent version of the article. View current version (07 NOV 2014)



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Description of the condition

The key feature of somatoform disorders is the presence of chronic, medically-unexplained physical symptoms (MUPS). This means that healthcare professionals are unable to find any pathological mechanism to medically explain the patient's physical complaints (Wessely 1999). Corresponding to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association 1994) and the International Classification of Diseases (ICD-10; World Health Organisation 1992), there are four somatoform diagnostic categories that include MUPS as their main indication:

  • somatisation disorder,
  • undifferentiated somatoform disorder,
  • somatoform autonomic dysfunction, and
  • pain disorder.

The current review will be confined to these four categories. Other somatoform diagnoses will not be considered because they either do not primarily focus on MUPS (hypochondriasis, body dysmorphic disorder), or the duration and chronic manifestation criteria are not specifically required (other somatoform disorders or somatoform disorders unspecified), or it is required that the physical symptoms are associated with a distressing event (conversion disorder).

Somatisation disorder depicts an extreme and chronic form of MUPS. To be diagnosed with this disorder, the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association 1994) requires an overall number of eight unexplained physical symptoms, with a chronic manifestation relating to at least four different organ systems: pain, gastrointestinal, sexual, and pseudoneurological symptoms. Physical symptoms should begin before the age of 30 years and must lead to healthcare utilisation or significant impairment in important areas of functioning. Diagnostic criteria for somatisation according to the ICD-10 are similar to those of DSM-IV. The only differences are that ICD-10 requires the duration of symptoms to be at least two years (independent of age at onset); that the lists of physical symptoms are structured in different ways; and that the patient persistently refuses to accept that his or her symptoms are unexplained by a medical condition.

A less stringent form of somatisation disorder is undifferentiated somatoform disorder, where medically unexplained physical symptoms must have persisted for at least six months. The diagnostic category 'somatoform autonomic dysfunction' is only registered in the ICD-10 and requires chronic symptoms especially related to the autonomic system. Finally, pain disorder involves the persistence of medically unexplained pain symptoms. In DSM-5 ( - the new revision of the DSM, due to be published in 2013 - the four mentioned somatoform diagnoses focusing on MUPS will be covered by the diagnostic category 'somatic symptom disorder'.

Apart from the categories defined in DSM-IV and ICD-10, over the years further 'abridged' diagnostic labels have been developed because the classic criteria of the international classification systems are difficult to use for research purposes. Whereas for somatisation disorder the criteria are considered to be too stringent, for undifferentiated somatoform disorder the threshold level is considered to be too low. Therefore, diagnostic labels such as abridged somatisation disorder or the somatic symptom index (SSI-4,6; Escobar 1987), multisomatoform disorder (Kroenke 1997), polysymptomatic somatoform disorder (Rief 1999), or bodily distress syndrome (Fink 2010), were developed. All of these constructs have received varying amounts of attention in research on somatoform disorders.

A recent European study based on general populations and using a stepwise multi-method approach, found the 12-month prevalence for somatoform disorders in general (including somatisation disorder, undifferentiated somatoform disorder, pain disorder, and hypochondrias) to be approximately 6.3% (range: 1.1% to 11%; Wittchen 2011; Wittchen 2005). Prevalence rates for the separate forms of somatoform disorders have been found to vary considerably. The 12-month prevalence rate for individuals fulfilling the stringent criteria of somatisation disorder was found to be low (range: 1.1% to 2.1%) among the European (Wittchen 2005) and American general populations (Robins 1991). However, in contrast, the lifetime prevalence rates for the less stringent categories of somatoform disorders such as undifferentiated somatoform disorder, somatoform autonomic dysfunction, or pain disorder were found to be much higher, ranging between 12% and 19% (Creed 2011; Fröhlich 2006; Grabe 2003; Jacobi 2004; Martin 2006; Meyer 2001; Robins 1991; Wittchen 1992).

Risk factors for developing chronic MUPS are female gender (e.g., Nimnuan 2001; Verhaak 2006) and low socioeconomic status (e.g., Jacobi 2004). The highest comorbidity rates have been found for anxiety disorders, affective disorders, and substance abuse (e.g., De Waal 2004; Fröhlich 2006; Kroenke 1997). Somatoform disorders in general are associated with excessive treatment and healthcare costs (Barsky 2005).

Etiological theories of somatoform disorders and MUPS in general are varied (Rief 2007; Witthöft 2010). One of the most important concepts is that of somatosensory amplification (Barsky 1990). The authors assume that individuals with a tendency to experience somatic sensations as intense, noxious, and disturbing amplify benign somatic sensations by mis-attributing them to serious illnesses and by focusing attention on them. Kirmayer and colleagues (Kirmayer 1997) expanded this perceptional-cognitive model by integrating social aspects (e.g., communication of distress with others, help-seeking behaviour). Another important model, focusing more on the perceptual process itself and its psychobiological correlates, is a signal-filtering model of MUPS (Rief 2005). It emphasises the interaction of biological and psychological processes in the perception of MUPS. Finally, Ursin 1997 and Yunus 2007 have postulated mechanisms of central sensitisation for explaining MUPS. Central sensitisation describes a plastic response of an increased efficacy in synapses in specific brain areas - especially in limbic structures - as a consequence of repeated use (Ursin 1997).


Description of the intervention

In addition to psychological therapy approaches (Kleinstäuber 2011), pharmacological agents are also used to treat somatoform disorders. In contrast to psychological therapies, however, the mechanisms of action of pharmacotherapy in somatoform disorders are still partly unclear.

Based on the findings of research on chronic pain syndromes such as neuropathic pain (Saarto 2007) and fibromyalgia (Häuser 2009; O'Malley 2000), or other syndromes of MUPS such as irritable bowel syndrome (IBS) (Ford 2009; Jackson 2000; Jackson 2006) or chronic fatigue syndrome (Pae 2009), antidepressants in particular have been used. Furthermore, findings from studies examining the effects of antidepressants on psychiatric comorbid conditions that are common in patients with somatoform symptoms (e.g., depression or anxiety disorders), also support the administration of antidepressant drugs in patients with somatoform disorders (Verdu 2008; Whitehead 2002).

Three groups of antidepressants are particularly relevant: tricyclic antidepressants (TCAs; e.g., amitriptyline, desimipramine, trimipramine, doxepine, opipramol), selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, escitalopram, sertraline, paroxetine, fluvoxamine or fluoxetine), and selective serotonin and norepinephrine reuptake inhibitors (SNRIs; e.g. venlafaxine, duloxetine). Another group of pharmacological agents used for the treatment of somatoform disorders is antiepileptic drugs. Here there are also parallels to the research on chronic pain, where efficacy in pain relief of anti-epileptics such as pregabalin (Moore 2009) or gabapentin (Moore 2011) has been demonstrated. For primarily pain-dominated somatoform symptoms such as headache, the efficacy of antipsychotics (e.g., olanzapine) has already been shown (Silberstein 2002). Finally, natural products such as St John's Wort are also used in the treatment of MUPS.

In Germany, a guideline for the treatment of non-specific functional or somatoform symptoms has recently been developed (AWMF 2012). The guideline recommends the use of different classes of antidepressants, particularly for severe syndromes dominated by pain symptoms and with or without comorbid depressive symptoms. For severe syndromes not determined by pain, the guideline recommends antidepressants only if there is comorbid depression. Furthermore, the guideline discourages the application of anxiolytic drugs, tranquillisers or hypnotics, and antipsychotics when there is no comorbid symptomatology that justifies the prescription of such agents. The TCA opipramol has been officially approved in Germany for the medical treatment of somatoform disorders ( It should be taken into consideration that current guidelines (e.g., AWMF 2012) in general do not recommend treating somatoform disorders with pharmacotherapy alone, but rather in combination with psychosocial interventions.


How the intervention might work



The mechanisms of action of antidepressants on somatoform symptoms remain unclear. Once more, parallels to syndromes such as IBS or fibromyalgia can be drawn. In these syndromes, patients have demonstrated increased prefrontal cortex activity with noxious stimulation. These are areas responsible for increased attention to a stimulus (Bonaz 2002; Drossman 2003). Furthermore, abnormal activity in brain areas involved with serotonin (5-HT) and norepinephrine (NE) have been observed in patients with somatoform symptoms. In addition, 5-HT and NE have been found to produce analgesic effects via inhibitory descending pain pathways (Jones 1991; Richardson 1990; Stahl 2002). Therefore, 5-HT and NE could be involved in suppression of somatic symptoms at the level of the spinal cord. This could explain why patients with IBS experience gastric and colonic distention as more painful than patients without the syndrome (Naliboff 1997). The same can be observed in patients with fibromyalgia: these patients have lower thresholds when they experience pain from noxious stimulation (Montoya 2005; Petzke 2005). Therefore, antidepressant action may involve processing pain on a central as well as peripheral level. Furthermore, antidepressants may alter pathophysiological mechanisms involved in somatoform symptoms and could have direct effects on different organ systems. For example, tricyclic antidepressants may slow gastrointestinal transit due to anticholinergic effects. This can improve diarrhoea-predominant IBS (Gorard 1994) in particular. Additionally, especially in the treatment of fatigue with antidepressants, it is speculated that immunoregulatory effects could play an important role (Kubera 2001; Maes 2001). Finally, a mechanism of action could be that antidepressants reduce comorbid psychiatric conditions such as depressive disorders, anxiety disorders and postraumatic stress (De Waal 2004). This, in turn, can influence symptom severity and functional impairment.


Anti-epileptic drugs

The mechanisms of action of anti-epileptic drugs on MUPS are also unclear. In neuropathic pain there is evidence that two antiepileptic drugs - gabapentin and pregabalin - bind calcium channels and modulate calcium influx (Urban 2005). Furthermore, they influence GABAergic neurotransmission (Gu 2002). Apart from anti-epileptic effects, this mode of action can also produce analgesic, anxiolytic, and sedative effects. Pregabalin is more potent than gabapentin and is therefore administered at lower doses.



The use of antipsychotics in somatoform disorders is based on their analgesic effects (Nix 1998). The way antipsychotics work to reduce pain is still unclear. It is possible that the modes of action vary between different agents. The analgesic effect could be mediated by opioid mechanisms, serotonin antagonism (Schreiber 1999), or activity at alpha2-adrenoreceptors (Silberstein 2002).


Natural products

Mechanisms of action are also unclear for natural products such as St John's Wort. Its administration in somatoform disorders is primarily based on diagnostic overlaps between depressive or anxiety and somatoform disorders (Linde 2009). Several studies on the efficacy of St John's Wort for mild depression could demonstrate an additional positive effect on somatoform symptoms such as headache or gastrointestinal complaints (e.g., Sommer 1993; Woelk 2000). The effect of Hypericum extracts, and especially hyperforin and adhyperforin, could be mediated by their function as potent but non-specific inhibitors of the synaptosomal reuptake of serotonin, norepinephrine, and dopamine (Butterweck 2003).


Why it is important to do this review

In addition to psychotherapeutic approaches, pharmacological agents are also often used in the treatment of somatoform disorders. Previously the efficacy of these agents has been mainly researched in patients with chronic pain where the use of specific medications has been judged critically. For example the authors of another Cochrane review (Seidel 2008), critically consider the application of antipsychotics for chronic painful conditions. They emphasise that the particularly strong extrapyramidal side effects and sedating effects have to be taken into consideration before they are prescribed. Although different pharmacological agents are part of treatment routines for patients with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications.

The intention of this meta-analysis is therefore to give an overview of: (1) the current status of research on the efficacy of pharmacological treatments for somatoform disorders, and (2) the acceptability of using medication to treat patients with somatoform disorders. It should also assist patients as well as providers in making optimal treatment decisions. Furthermore, it should disclose the shortcomings of previous research in pharmacotherapy for somatoform disorders and help to stimulate further research in this area. In this way the current review adds to a portfolio of five Cochrane reviews covering somatoform disorders (the other four being Hoedeman 2010; Ipser 2009; Ruddy 2005; Thomson 2007).



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Criteria for considering studies for this review


Types of studies

We will include randomised controlled trials (RCTs) and cluster-randomised controlled trials (CRCTs).

We will also include cross-over trials, but only data from the first randomisation period will be included in the review.

We will exclude quasi-randomised trials (e.g., allocation to the study group by day of the week).

In the case that treatment outcome data are absent, the trial will be excluded from meta-analysis but will be included as part of the narrative literature review.


Types of participants


Participant characteristics

Participants must be between 18 and 65 years old. There will be no restriction on gender or culture.



Participants must meet the requirements for diagnosis of a somatoform disorder, based on chronic, multiple, medically unexplained physical symptoms, according to DSM-III (American Psychiatric Association 1980), DSM-IV-TR (American Psychiatric Association 2000), ICD-9 (World Health Organisation 1975), or ICD-10 (World Health Organisation 1992). See  Table 1 for an overview of all diagnostic categories of somatoform disorders and a clear indication of whether or not they are eligible for this review.

The diagnoses have to be made on the basis of a structured clinical interview such as the Structured Clinical Interview for Mental Disorders (SCID; First 1996), the World Health Organisation Composite International Diagnostic Interview (CIDI; World Health Organisation 1990), the M.I.N.I. International Neuropsychiatric Interview Plus (Mini-Plus; Sheehan 1998) or diagnostic checklists such as the International Diagnostic Checklists (IDCL; Janca 1996). A medical assessment of the physical symptoms is required to rule out the possibility that the physical symptoms and their intensity can be explained sufficiently by a medical condition.

In DSM-5 the four diagnostic categories that are defined among the inclusion criteria for the current review will be summarised into one category - 'somatic symptom disorder'. Therefore, the diagnostic inclusion criteria for the current review will not need to be revisited following the publication of DSM-5.



We will include people with certain co-morbidities, but the somatoform disorder has to be the primary diagnosis.

Studies that include participants with co-morbid psychiatric disorders will be included, with the exception of studies in which participants suffer from a co-morbid psychosis or dementia, which will be excluded.

Studies that examine the efficacy of a pharmacotherapy in a group of participants diagnosed with only one specific functional syndrome (e.g., irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) will be excluded.



There will be no restriction on setting.


Types of interventions


Experimental interventions

Eligible studies will include one or more of the following experimental interventions:

  1. Tricyclic antidepressants (e.g., amitriptyline)
  2. Newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine), serotonin and noradrenaline reuptake inhibitors (SNRIs, e.g. venlafaxine), and reversible inhibitors of monoamine oxidase type A (RIMAs, e.g. moclobemide)
  3. Any other antidepressants such as irreversible mono-amine oxidase inhibitors (MAOIs; e.g., bupropion)
  4. Antiepileptics (e.g., pregabalin, gabapentin)
  5. Natural products (e.g., St John's Wort)
  6. Antipsychotics
  7. Other pharmacological agents (e.g., benzodiazepines)


Comparator interventions

The following comparator interventions will be accepted:

  1. Placebo
  2. Treatment as usual
  3. Another medication


Types of outcome measures


Primary outcomes

1. Reduction of the level of severity/intensity of medically unexplained physical symptoms (MUPS)

If a validated self-report scale is used, this will be considered the primary outcome. Validated scales for the assessment of MUPS considered for this review are: Screening for Somatoform Symptoms (SOMS; Rief 2008); and Bradford Somatic Inventory (BSI; Mumford 1991). If no validated scales are available, component subscales of validated standardised instruments for the assessment of general psychopathology or general health status will also be accepted, for example the subscale 'Somatisation' of the Patient Health Questionnaire-15 (PHQ-15; Kroenke 2002); the subscale 'Somatisation' of the Symptom Checklist-90-R (SCL-90-R; Derogatis 1983); or the Brief Symptom Inventory (BSI; Derogatis 1992). Where unvalidated or visual analogue self-report scales have been used, we will decide which scale most closely approximates MUPS. This will be done by one of the co-authors (WH) who is an expert in regard to somatoform disorders and clinical diagnostics, but who will not directly be involved in the process of study selection or data extraction and management, so that he can be blinded to the results. Clinician-rated severity of MUPS will be examined separately and will not be aggregated together with self-report outcomes into one effect size index.

2. Acceptability

The proportion of patients who dropped out during the experimental as well as the comparator intervention. This rate will be calculated as a proportion of the total number of randomised patients.


Secondary outcomes

3. Depression and anxiety: either (i) validated self-report instruments, e.g., Beck Depression Inventory (BDI; Beck 1961), Beck Anxiety Inventory (BAI; Beck 1990), or (ii) clinician-rated, e.g. Hamilton Depression Rating Scale (HDRS; Hamilton 1960), Hamilton Anxiety Rating Scale (HARS; Hamilton 1959).

4. Dysfunctional cognitions, emotions or behaviours/patient-rated: validated self-report scales, e.g., the Whiteley Index (WI; Pilowsky 1967), Illness Attitude Scales (IAS; Kellner 1986), Scale for the Assessment of Illness Behavior (SAIB; Rief 2003), Cognitions About Body and Health Questionnaire (CABAH; Rief 1998).

5. Adverse effects: When possible, the most common drug-related adverse effects (defined as effects that occur in at least 10% of patients receiving medication) as well as significant differences in the rate of occurrence of drug-related adverse events between medication and control groups, will be described as part of the narrative literature review. As a limitation to interpreting these adverse effects, we note that the inclusion of RCT or CRCT studies will not be sufficient to gain information about the more rare or long-term adverse outcomes.

6. Treatment response (responder versus non-responder): Clinician-rated Clinical Global Impression Scale - Improvement item (CGI-I; Guy 1976); responders are defined on this scale as those with a score of "1 = very much improved" or "2 = much improved". Alternatively, the number of patients who responded to the treatment according to the author's definition. Response rates will be calculated out of the total number of all randomised patients.

7. Functional disability and quality of life: (i) validated clinician-rated scales, e.g. Global Assessment of Functioning (GAF; American Psychiatric Association 1994) or (ii) validated self-report instruments, e.g. Sheehan Disability Scale (SDS; Sheehan 1983); Short Form 36 Questionnaire (SF-36; Ware 1992).


Timing of outcome assessment

The primary and secondary outcomes are classified as assessed: i) post treatment, ii) within 12 months post treatment, or iii) more than 12 months post treatment.


Search methods for identification of studies

The Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR)
The Cochrane Depression, Anxiety and Neurosis Group (CCDAN) maintain two clinical trials registers at their editorial base in Bristol, UK: a references register and a studies-based register. The CCDANCTR-References Register contains over 31,500 reports of RCTs in depression, anxiety and neurosis. Approximately 65% of these references have been tagged to individual, coded trials. The coded trials are held in the CCDANCTR-Studies Register and records are linked between the two registers through the use of unique Study ID tags. Coding of trials is based on the EU-Psi coding manual, using a controlled vocabulary; please contact the CCDAN Trials Search Coordinator for further details. Reports of trials for inclusion in the Group's registers are collated from routine (weekly), generic searches of MEDLINE (1950-), EMBASE (1974-) and PsycINFO (1967-); quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL) and review-specific searches of additional databases. Reports of trials are also sourced from international trials registers c/o the World Health Organization's trials portal (the International Clinical Trials Registry Platform (ICTRP)), pharmaceutical companies, the handsearching of key journals, conference proceedings and other (non-Cochrane) systematic reviews and meta-analyses.

Details of CCDAN's generic search strategies (used to identify RCTs) can be found on the Group's website.


Electronic searches

1. The CCDANCTR Studies Register will be searched using the following terms:
Condition = “Somatization Disorder”
Records will be manually screened for pharmacological interventions.

2. The CCDANCTR-References Register will be searched for additional untagged references, using a more sensitive set of free-text terms:
(somatization or somatisation or hysteri* or briquet or polysymptom* or multisomatoform or somatizer* or (multiple and (MUPS or “medically unexplained” or “unexplained symptoms” or “physical symptoms” or “symptom diagnos*”)))
Records will be manually screened for pharmacological interventions.

3. To ensure no studies have been missed, complementary searches will be conducted by the author team on the following bibliographic databases, using relevant subject headings (controlled vocabularies) and search syntax, appropriate to each resource: (a) PsycINFO (all years, Appendix 1) (b) MEDLINE via Pubmed (from 1950 onwards), (c) EMBASE (from 1974 onwards), (d) Web of Science (from 1945 onwards), and (e) PSYNDEX (from 1977 onwards).

To identify ongoing trials, we will search the register (, the Current Controlled Trials metaRegister of Controlled Trials-active registers (mRCT;, and the WHO International Clinical Trials Registry Platform Search Portal (

No language or date restrictions will be applied. Search strategies will be revisited after the publication of DSM-5.


Searching other resources


Grey literature

We will search the ProQuest Dissertation & Theses Database, INIST, and BIOSIS Previews for trials published in dissertations or theses, or other sources of grey literature.



Proceedings of the following conferences over the last five years will be handsearched:

American Psychiatric Association (APA) Annual Meeting; World Congress of The International College of Neuro-Psychopharmacology (CINP); European College of Neuropsychopharmacology (ECNP) Congress; International Congress of Behavioral Medicine (ICBM); European Conference on Psychosomatic Research (ECPR); Annual Meeting of the European Association for Consultation-Liaison Psychiatry and Psychosomatics (EACLPP); Congress of the German Association for Psychiatry, Psychotherapy, and Neurology (DGPPN).


Reference lists

We will search reference lists of all potentially relevant papers and of systematic reviews or meta-analyses for further relevant studies. Systematic reviews or meta-analyses will be identified using appropriate search filters in Pubmed and EMBASE.



We will ask experts in the field of somatoform disorders, as well as authors who have published studies on pharmacotherapy or other therapies for MUPS, if they know any published or unpublished or ongoing trials meeting the criteria of the current review.


Data collection and analysis


Selection of studies

In a first step, titles and abstracts of reports that are identified from the literature search will be screened independently by two authors (MK, MW). Those studies that obviously do not fulfil inclusion criteria at this stage of the screening process will be discarded. Potentially relevant articles will be retrieved for full-text assessment. In the next step, the main text of these retrieved trials will be assessed independently by the same two authors for eligibility. Disagreements will be resolved by consensus, if necessary with the involvement of a third author (WH). Non-congruence in selection of trials will be reported as percentage disagreement. Studies for which additional information is required in order to determine their suitability for inclusion in the review will be listed in the 'Studies awaiting assessment' table in the Review Manager (RevMan) software. One author (MK) will check the reference lists of articles that are retrieved after the second stage of the selection process. The review authors will not be blinded to the name(s) of the study author(s). Reasons for exclusion will be reported in the 'Characteristics of Excluded Studies' table.

All decisions that are made throughout the review process, along with the number of references and studies found, will be recorded and will be presented in a PRISMA flow diagram at the end of the review (Moher 2009).


Data extraction and management

Data extraction will be conducted independently by the first review author (MK) and a research assistant. A data extraction form will be prepared a priori and will be piloted before use. The research assistant will have had training in completing the data extraction form. We will assess characteristics regarding the trial, participants, methods, intervention and outcome details, summary statistics, and associated commentaries. If necessary, we will contact authors of reports for clarification or additional information. We will organise data using the most recent version of RevMan software. Disagreements will be negotiated with a further author (MW or WH). We will extract the following information:

  1. Characteristics of the trial: primary researcher, publication year, status of publication, language of publication, source of funding, study design, length of follow-up.
  2. Characteristics of participants: source of sample, sample size, gender, age, number of drop outs, nationality, applied diagnostic criteria, somatoform diagnosis, comorbidity, comorbid diagnoses, screening procedure (e.g., interview), screening instruments, inclusion and exclusion criteria, mean length of time since diagnosis of a somatoform disorder, previous treatments.
  3. Characteristics of intervention: category of medication, agent, treatment setting, dose of medication, frequency of intake, mode of administration of medication, period over which the medication was administered, number of patients that dropped out due to adverse effects or inefficacy of treatment, most common drug-related adverse effects, details of concurrent treatments (e.g., psychotherapy).
  4. Details of methodology: number of centres involved; number of participants that were not included in the analyses (lost to follow-up); whether blinding occurred for assessors, participants, or those who administered medication.
  5. Outcome measures: primary and secondary outcome measures, summary statistics of continuous data (mean, standard deviation) and dichotomous data (number of responders), timing of outcome assessments, intention-to-treat analysis (ITT) (with last observation carried forward (LOCF)) or observed cases/completer analysis, other methods of estimating the outcome for participants who dropped out (e.g., mixed effect analyses).

As medication classes can all have different effects, we will stratify the comparisons by medication class. The following main comparisons are therefore planned for each class of medication:

  1. Medication versus placebo
  2. Medication versus usual treatment
  3. Medication versus another medication.


Assessment of risk of bias in included studies

The first review author (MK) and a research assistant will independently assess the risk of bias within each included study. The assessment of risk of bias will be based on a tool in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a), which includes six categories. The following judgments have to be passed with consensus of the review author and the research assistant for each of these categories:

  1. Random sequence generation: Was the method to generate the sequence of randomised allocation adequate to produce comparable groups?
  2. Allocation concealment: Was the allocation concealed adequately so that intervention allocations could not have been foreseen in advance of or during enrolment?
  3. Blinding: a) Was knowledge of the allocation of treatment of the participant and study personnel adequately prevented during the study? b) Was knowledge of the allocation of treatment of the outcome assessor(s) adequately prevented during the study? Any measures applied to blind participants, personnel and outcome assessors will be described. The assessment will be made separately for each outcome domain.
  4. Incomplete outcome data: Were incomplete outcome data adequately addressed? The completeness of outcome data will be described, including attrition and exclusions from analyses. If there are attritions and exclusions in the treatment and control group they will be reported, along with the reasons. If the review authors conducted any re-inclusions in their analyses, this will also be reported. The assessment will be made separately for each outcome domain.
  5. Selective reporting: Are reports of the study free of suggestion of selective outcome reporting?
  6. Other sources of bias: Was the study apparently free of other sources that could produce risk of bias?

In order to assess risk of bias in the following specific types of study design, additional judgments have to be passed:

  • Multiple-intervention studies: Are data presented for each of the groups to which participants were randomised?
  • Cross-over trials: a) Is it clear that the order of receiving a treatment was randomised? b) Are unbiased data from the first treatment-period available?
  • Cluster-randomised controlled trials: a) Were individuals recruited to the trial after the clusters had been randomised? b) Were methods of stratified or pair-matched randomisations of clusters used? c) Were adequate statistical analyses (taking clustering into account) used?

We will use the following scale to rate each of the categories: 'High' (high risk of bias); 'Low' (low risk of bias); 'Unclear' (uncertain risk of bias).

Disagreements regarding the ratings will be negotiated with a further author (MW or WH). If necessary we will contact study authors for further information.


Measures of treatment effect


Dichotomous data

For computing treatment effects based on dichotomous data, the pooled risk ratio (RR) with 95% confidence interval (CI) will be used for each comparison. The number needed to treat to benefit (NNTB) will be calculated for every class of pharmacological agent for which a statistically significant treatment effect is found. The risk ratio estimate and the control risk from the placebo group will therefore be used.


Continuous data

We will collect the mean score, standard deviation (SD) and the number of participants at endpoint and follow-up. These values for the single trials will be pooled as follows: assuming that at least two studies using the same scale are available, we will calculate the mean difference (MD) with a 95% CI between experimental and comparator intervention at endpoint and follow-up. In case measures of an outcome domain will vary across studies the standardised mean difference (SMD) with 95% CI will be used. Specific attention has to be paid to the secondary outcome 'functional disability and quality of life' because the direction of corresponding scales can differ. Whereas an increase of scales of functional disability usually indicates deterioration, an increase of scales of quality of life often indicates improvement. The SMD method does not correct for such differences in the direction of the scale. In this case the mean values from one set of studies will be multiplied by –1 to ensure that all the scales point in the same direction.


Unit of analysis issues


Cluster-randomised controlled trials

In order to avoid unit-of-analysis errors for trials in which incorrect statistical analyses were conducted, we will perform approximate analyses based on inflating standard errors. Before data are entered into RevMan for meta-analytic calculations, the standard error of the effect estimate (from an analysis not taking into to account the clustering) will be multiplied by the square root of the so-called design effect. The design effect is 1 + (M – 1) ICC, where M is the average cluster size and ICC is the intracluster correlation coefficient. We will assume a common design effect across intervention groups. If the ICC is not available in the published report, we will use an external estimate obtained from similar studies or another external resource. The meta-analysis using the inflated variances may be performed using RevMan and the generic inverse-variance method.


Studies with multiple treatment groups

In trials comparing the efficacy of more than one medication for somatoform disorders, three aspects will be considered:

  1. If the different medications are of the same class of chemical agent (e.g. tricyclic antidepressants), the different experimental conditions are summarised into a single group that will be compared with the control group. For continuous data, means and standard deviations are pooled across all of the treatment arms as a function of the number of participants in each arm. For dichotomous outcomes, both the sample sizes and the numbers of people with events will be summed across groups.
  2. If the different medications are of different classes of chemical agents (e.g. selective serotonin reuptake inhibitors versus tricyclic antidepressants), each pair-wise comparison is included separately, but the 'shared group' will be divided into two or more groups (according to the number of intervention groups) with smaller sample size. For dichotomous outcomes, both the number of events and the total number of patients will be divided up. For continuous outcomes, only the total number of participants will be divided up and the means and standard deviations left unchanged. Although this method only partially overcomes the unit-of-analysis error, an advantage of this approach is that investigations of heterogeneity across intervention arms are possible.
  3. In the case of data from trials employing multiple fixed doses of medication, the different experimental groups will be summarised into one group corresponding to the pooling procedure of the previous section. The pooling of outcome data will be restricted to those treatment arms that employ at least the minimum dose recommended by clinical guidelines or experts, in order to reduce the influence of data from arms that employ doses unlikely to have a clinical effect.


Cross-over trials

Cross-over trials will only be included in meta-analytical calculations if it is possible to extract relevant data of the treatment and control group from the first treatment period.


Dealing with missing data

In the case of a missing continuous data summary, statistics based on mixed effects models (ME) are preferred, followed by statistics based on intention-to-treat (ITT) analysis with last observation carried forward (LOCF) and on observed cases (OC). This is in accordance with the finding that ME-methods are more robust to bias than LOCF (Verbeke 2000). If standard deviations are not available directly, we will attempt to calculate them from t-, F-, P, or CI-values (Higgins 2011b), or standard errors (Altman 1996).

In the case of missing dichotomous data, ITT analysis will be applied, in which it will be assumed that patients who dropped out after randomisation had a negative outcome. According to Gamble and Hollis (Gamble 2005), sensitivity analyses for dichotomous data will also be conducted: best/worst case scenarios will be calculated for the clinical response outcome, in which it will be assumed that drop outs in the active treatment group had positive outcomes and those in the control group had negative outcomes (best case scenario), and that drop outs in the active treatment group had negative outcomes and those in the control group had positive outcomes (worst case scenario).

If data are not in a suitable format or if relevant data are not available, we will try to contact trial authors to obtain further information. Reasons for missing data will be reported where they are provided in the published trials. Where data cannot be included, we will report a qualitative summary of the results in the text of the review.


Assessment of heterogeneity

Statistical heterogeneity will first be assessed visually by inspecting forest plots of standardised mean effect sizes and of relative risk. Furthermore, we will apply a Chi2 test to assess heterogeneity. The test has low power in general but especially when the sample size of the included studies is low or there are only a few included studies. A P value of 0.10 will therefore be used to determine statistical significance in a conservative way. Another problem of the Chi2 statistic is that it indicates only significance or non-significance but does not give any information about the level of heterogeneity. For this reason a further statistic will be used: the I² statistic. I² describes the percentage of variability in effect estimates that is due to heterogeneity rather than sampling error. We will use conventions of interpretation that were defined by Higgins (Higgins 2011a). In the case of substantial levels (50% ≤ I² ≤ 90%) and considerable levels (75% ≤ I² ≤ 100%) of heterogeneity, data will be examined by subgroup and sensitivity analyses (see below) - in regard to different aspects of clinical and methodological heterogeneity.

Especially for the assessment and examination of clinical heterogeneity, subgroup analyses (see Subgroup analysis and investigation of heterogeneity) are planned in regard to the following pre-specified characteristics: class of medication, comorbidity, gender, source of funding for the trial, and source of outcome rating.


Assessment of reporting biases

In order to prevent publication bias, every attempt will be made to include unpublished trials (e.g., by searching online trial registries or registries of unpublished doctoral theses). In order to assess for a publication bias, we will implement funnel plots (effect versus standard error of the effect size) when a sufficient number of trials are available (according to recommendations of the Cochrane Handbook for Systematic Reviews of Interventions there should be at least 10 studies; Sterne 2011). For the analysis and the interpretation of the funnel plots other reasons for asymmetry besides publication bias (e.g., differences in methodological quality, true heterogeneity in intervention effects) have to be considered.


Data synthesis

In the case that two or more studies that are eligible for inclusion are found per comparison category (see Data extraction and management), and that these studies measure the same outcome construct, we will perform a meta-analysis of the results. Data will be entered into a recent version of RevMan software by one author (MK). Dichotomous and continuous treatment effects will be obtained from a random-effects model. However the fixed-effect model will be specified as sensitivity analysis in order to informally compare the results. Where heterogeneity analysis indicates significant heterogeneity, we will perform subgroup analysis. If this analysis reveals a significant difference between subgroups, we will only report results of the corresponding subgroup meta-analysis. When the subgroup analysis provides no explanation of significant heterogeneity, we will only present a forest plot without meta-analytic results. The calculation of the averaged effect size for each (sub)group as well as the 95% CI is based on the inverse-variance method. This will be reported for the post-treatment assessment. If data are available, the summarised statistic will also be reported for follow-up assessment (< 12 months after post treatment or ≥12 months after post treatment).


Subgroup analysis and investigation of heterogeneity

Although subgroup analyses have to be treated with caution as they are rather hypothesis-forming than -testing, we will perform a priori defined analyses in order to explore whether methodological and clinical differences between the trials have systematically influenced the differences that were observed in the treatment outcomes. If there are data available we plan the following comparisons:

1. Comorbidity

As known from other mental disorders, comorbid psychological problems can moderate the efficacy of a medication. Therefore we will compare the effects of pharmacotherapy for somatoform disorder patients, with or without comorbid mental disorders.

2. Gender

Sex differences have been found in the absorption, metabolism, and excretion of many medications (Clayton 2005). Therefore we will examine gender differences in the efficacy of pharmacotherapy for somatoform disorders.

3. Source of funding

Industrial funding of pharmacological trials can be associated with conflicts of interest for the trial conductors. Therefore we plan subgroup analyses in order to examine differences in the efficacy of medications between trials funded versus not funded by industry.

4. Source of outcome rating

In previous studies (e.g. Rief 2009), it has been demonstrated that results based on patient-rated measures, or on clinician-ratings, can differ considerably from each other. Therefore, we plan subgroup analyses relating to different sources of outcome rating.


Sensitivity analysis

We will conduct sensitivity analyses in order to determine whether conclusions are robust to decisions made during the review process (e.g. the inclusion or exclusion of specific studies or choice of the method of analysis). It should be verified that the results of the review do not depend on specific decisions that were made during the review process. As part of a sensitivity analysis we will compare effect sizes based on random-effect and fixed-effects analyses. If sufficient data are available, we will examine the following aspects in further sensitivity analyses:

  • Exclusion of studies with unclear allocation concealment.
  • Exclusion of studies with unclear methods of blinding of outcome assessors.
  • Exclusion of studies with unclear methods of sequence generation.
  • Exclusion of CRCTs.
  • Exclusion of CRCTs for which ICCs were used.
  • For continuous outcomes only: exclusion of results based on mixed effects models or on intention-to-treat approach (LOCF).
  • For dichotomous outcomes only: best/worst case analyses (see also Dealing with missing data).
  • For dichotomous outcomes only: exclusion of results based on available/observed cases.
  • Exclusion of studies with a drop out higher than 20%.


Summary of findings    [Explanations]

In order to summarise the main findings of the review in a simple tabular format, we will prepare a 'Summary of findings' table. The table will include a list of the seven outcomes specified under Types of outcome measures. The table will summarise effects based on a population of patients fulfilling inclusion criteria for this review (see Types of participants). Furthermore the table will address only the comparison 'pharmacotherapy for somatoform disorders versus placebo' at post treatment because this comparison is expected to be the most important one in the current review. For dichotomous outcomes (acceptability, treatment response) we will report an assumed and corresponding absolute risk with 95% CI as well as a relative risk - corresponding to the odds ratio with 95% CI obtained from the meta-analysis. For continuous outcomes (level of severity/intensity of MUPS, dysfunctional cognitions/emotions/behaviours, anxiety and depression, functional disability/quality of life), in the column of assumed and corresponding risk we will present a difference in means or standardised difference in means with its 95% CI. We will use footnotes in order to specify the source or rationale for each assumed and corresponding risk. In order to assess the quality of body of evidence for each outcome we will use the GRADE approach (GRADEpro software; Schünemann 2008), providing a transparent procedure to classify the quality of evidence as 'high', 'moderate', 'low', and 'very low'. Judgements other than of 'high' quality will be made transparent using footnotes or the Comments column in the 'Summary of findings' table.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Special thanks to CCDAN's Trials Search Co-ordinator for assistance in developing search strategies for our review, and to Kim Jones for the proofreading.

CRG Funding Acknowledgement:

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Depression, Anxiety and Neurosis Review Group. 


The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.



  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Appendix 1. OVID PsycINFO search

[RCT Filter]
1. treatment effectiveness
2. clinical
3. mental health program
5. placebo*.ti,ab.
6. randomly.ab.
7. randomi#ed.ti,ab.
8. trial.ti,ab.
9. ((singl* or doubl* or trebl* or tripl*) adj3 (blind* or mask* or dummy)).mp.
10. (control* adj3 (trial* or study or studies or group*)).ti,ab.
11. factorial*.ti,ab.
12. allocat*.ti,ab.
13. assign*.ti,ab.
14. volunteer*.ti,ab.
15. (crossover* or cross over*).ti,ab.
16. (quasi adj (experimental or random*)).mp.
17. "2000".md.
18. or/1-17
19. exp somatization/
20. hysteria/
21. (somatiz* or somatis* or hysteri* or briquet or polysymptom* or poly symptom* or multisomat* or multi somat*).mp.
22. (multiple and (MUPS or medically unexplained or unexplained symptoms or physical symptoms or symptom diagnos*)).mp.
23. or/19-22
[Pharmacotherapies (broad, top level terms)]
24. exp Pharmacology/
25. exp Drugs/
26. exp Drug Therapy/
27. "3340".cc.
28. (drug* or pharma* or psychopharma* or psycho pharma* or psychotropic* or psycho tropic* or antipsychotic* or anti psychotic* or antiepileptic* or anti epileptic* or neuroleptic* or anticonvuls* or anti conculs* or antiemetic* or anti emetic* or hypnotic*).mp.
29. (antidepress* or anti depress* or MAOI* or monoamine oxidase inhibit* or ((serotonin or norepinephrine or noradrenaline or nor epinephrine or nor adrenaline or neurotransmitt* or dopamine*) and (uptake or reuptake or re-uptake)) or noradrenerg* or antiadrenergic or anti adrenergic or SSRI* or SNRI* or TCA* or tricyclic* or tetracyclic* or heterocyclic*).mp.
30. (anxiolytic* or ((anti anxiety or antianxiety) adj1 (drug* or agent*)) or tranquili#er* or sedative*).mp.
31. exp "Medicinal Herbs and Plants"/
32. exp Dietary Supplements/
33. (nutraceutical* or herbal).mp.
34. or/24-33
35. (18 and 23 and 34)

"2000".md. = Methodology: 'Treatment Outcome/Clinical Trial'
"3340".cc. =Concept Code: 'Clinical Psychopharmacology'


Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Preparation of the protocol:

Maria Kleinstäuber: developed and drafted the protocol.

Michael Witthöft, Andrés Steffanowski, Michael Lambert, Günter Meinhardt, Klaus Lieb, Wolfgang Hiller: supervised preparation of the protocol and gave feedback on the draft version of the protocol.

Preparation of the review:

Maria Kleinstäuber and Michael Witthöft will independently review titles and abstracts in the first step and will screen full texts regarding eligibility of studies for the review in the second step. Maria Kleinstäuber and Michael Witthöft will independently appraise the quality of the included studies. Maria Kleinstäuber and a research assistant trained in the data extraction procedure will independently extract data of the included studies. Andrés Steffanowski, Michael Lambert, Günter Meinhardt, Klaus Lieb, and Wolfgang Hiller will supervise the preparation of the review process and will arbitrate in the case of disagreements.


Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Maria Kleinstäuber: none known

Michael Witthöft: none known

Andrés Steffanowski: none known

Michael Lambert: none known

Günter Meinhardt: none known

Klaus Lieb: KL is a board-certified cognitive behaviour therapist with special interest in schema therapy. He has been involved in trials investigating inpatient DBT (Bohus 2004) and inpatient SFT (Reiss et al., in press)

Wolfgang Hiller: none known.


Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Internal sources

  • Johannes Gutenberg-University of Mainz, Germany.


External sources

  • No sources of support supplied


Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
Altman 1996
American Psychiatric Association 1980
  • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM III). 3rd Edition. Washington, DC: American Psychiatric Press, 1980.
American Psychiatric Association 1994
  • American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders (DSM IV). 4th Edition. Washington, DC: American Psychiatric Press, 1994.
American Psychiatric Association 2000
  • American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders (DSM-IV-TR). 4th edition, text revision. Washington, DC: American Psychiatric Press, 2000.
AWMF 2012
  • Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. Guideline for the treatment of patients with non-specific, functional and somatoform physical complaints [Leitlinie zum Umgang mit Patienten mit nicht-spezifischen, funktionellen und somatoformen Körperbeschwerden]. AWMF 2012.
Barsky 1990
Barsky 2005
Beck 1961
Beck 1990
  • Beck AT, Steer RA. Beck Anxiety Inventory Manual. San Antonio, TX: The Psychological Corporation, Harcourt Brace, 1990.
Bonaz 2002
  • Bonaz B, Baciu M, Papillon E, Bost R, Gueddah N, Le Bas JF, et al. Central processing of rectal pain in patients with irritable bowel syndrome: An fMRI study. American Journal of Gastroenterology 2002;97:654-61.
    Direct Link:
Butterweck 2003
Clayton 2005
Creed 2011
  • Creed F, Barsky AJ, Leiknes KA. Epidemiology: prevalence, causes and consequences. In: Creed F, Henningsen P, Fink P editor(s). Medically Unexplained Symptoms, Somatisation and Bodily Distress. New York: Cambridge University Press, 2011.
De Waal 2004
  • de Waal MW, Arnold IA, Eekhof JA, van Hemert AM. Somatoform disorders in general practice: prevalence, functional impairment and comorbidity with anxiety and depressive disorders. British Journal of Psychiatry 2004;184:470-6.
Derogatis 1983
  • Derogatis LR. The SCL-90-R Manual. Scoring and Administration Procedures for the SCL-90-R. Baltimore, MA: John Hopkins University School of Medicine, 1983.
Derogatis 1992
  • Derogatis LR. The Brief Symptom Inventory (BSI): Administration, Scoring, and Procedures Manual II. Baltimore, MD: Clinical Psychometric Research, 1992.
Drossman 2003
  • Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB, Duncan S, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003;125:19-31.
Escobar 1987
Fink 2010
  • Fink P, Schröder A. One single diagnosis, bodily distress syndrome, succeeded to capture 10 diagnostic categories of functional somatic syndromes and somatoform disorders. Journal of Psychosomatic Research 2010;68:415-26.
First 1996
  • First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). New York: New York State Psychiatric Institute, Biometrics Research, 1996.
Ford 2009
  • Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367-78.
Fröhlich 2006
  • Fröhlich C, Jacobi F, Wittchen HU. DSM-IV pain disorder in the general population - an exploration of the structure and threshold of medically unexplained pain symptoms. European Archives of Psychiatry and Clinical Neuroscience 2006;256:187-96.
Gamble 2005
Gorard 1994
Grabe 2003
Gu 2002
Guy 1976
  • Guy W. Clinical global impressions. ECDEU Assessment Manual for Psychopharmacology, revised (DHEW Publ. No. ADM 76-338). Rockville, MD: National Institute of Mental Health, 1976:218-22.
Hamilton 1959
Hamilton 1960
Higgins 2011a
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from, 2011.
Higgins 2011b
  • Higgins JPT, Deeks JJ. Selecting studies and collecting data. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from, 2011.
Hoedeman 2010
Häuser 2009
Ipser 2009
Jackson 2000
  • Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. American Journal of Medicine 2000;108:65-72.
Jackson 2006
Jacobi 2004
  • Jacobi F, Wittchen HU, Holting C, Hofler M, Pfister H, Muller N, et al. Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS). Psychological Medicine 2004;34:597-611.
Janca 1996
Jones 1991
Kellner 1986
  • Kellner R. Somatization and Hypochondriasis. New York: Praeger-Greenwood Publishers, 1986.
Kirmayer 1997
  • Kirmayer LJ, Looper KJ, Taillefer, S. Somatoform disorders. In: Turner SM, Hersen M editor(s). Adult Psychopathology and Diagnosis. 4th Edition. New York: John Wiley, 2003:420-75.
Kleinstäuber 2011
  • Kleinstäuber M, Witthöft M, Hiller W. Efficacy of short-term psychotherapy for multiple medically unexplained physical symptoms: a meta-analysis. Clinical Psychology Review 2011;31(1):146-60.
Kroenke 1997
  • Kroenke K, Spitzer RL, deGruy RV, Hahn SR, Linzer M, Williams JB. Multisomatoform disorder. An alternative to undifferentiated somatoform disorder for the somatizing patient in primary care. Archives of General Psychiatry 1997;54:352-8.
Kroenke 2002
Kubera 2001
  • Kubera N, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. Anti-inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio. Journal of Clinical Psychopharmacology 2001;21:199-206.
Linde 2009
Maes 2001
Martin 2006
Meyer 2001
  • Meyer C, Rumpf HJ, Hapke U, John U. Prevalence of DSM-IV psychiatric disorders including nicotine dependence in the general population: results from the Northern German TACOS study. Neurology Psychiatry and Brain Research 2001;9:75-80.
Moher 2009
Montoya 2005
Moore 2009
Moore 2011
  • Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD007938.pub2]
Mumford 1991
  • Mumford DB, Bavington JT, Bhatnagar KS, Hussain Y, Mirza S, Naraghi MM. The Bradford Somatic Inventory - a multiethnic inventory of somatic symptoms reported by anxious and depressed patients in Britain and the Indo-Pakistan subcontinent. British Journal of Psychiatry 1991;158:379-86.
Naliboff 1997
Nimnuan 2001
Nix 1998
  • Nix WA. What is certain in pain therapy? The analgesic potency of neuroleptics in the treatment of chronic pain. A meta-analysis [Was ist gesichert in der Schmerztherapie? Haben Neuroleptika eine analgetische Potenz? Eine Metaanalyse]. Schmerz 1998;12:30-8.
O'Malley 2000
Pae 2009
  • Pae CU, Marks DM, Patkar AA, Masand PS, Luyten P, Serretti A. Pharmacological treatment of chronic fatigue syndrome: focusing on the role of antidepressants. Expert Opinion on Pharmacotherapy 2009;10:1561-70.
Petzke 2005
Pilowsky 1967
Richardson 1990
Rief 1998
Rief 1999
Rief 2003
Rief 2005
Rief 2007
Rief 2008
  • Rief W, Hiller W. SOMS Screening for Somatoform Disorders. [SOMS. Das Screening für Somatoforme Störungen. Manual zum Fragebogen]. 4th Edition. Bern, Switzerland: Huber, 2008.
Rief 2009
Robins 1991
  • Robins LN, Regier DA. Psychiatric disorders in America: The Epidemiological Catchment Area Study. New York: The Free Press, 1991.
Ruddy 2005
Saarto 2007
Schreiber 1999
  • Schreiber S, Getslev V, Backer MM, Weizman R, Pick CG. The atypical neuroleptics clozapine and olanzapine differ regarding their antinociceptive mechanisms and potency. Pharmacology Biochemistry and Behavior 1999;64:75-80.
Schünemann 2008
  • Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, et al. Interpreting results and drawing conclusions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from, 2011.
Seidel 2008
Sheehan 1983
  • Sheehan DV. The Anxiety Disease. New York: Scribner, 1983.
Sheehan 1998
  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry 1998;59:22-33.
Silberstein 2002
Sommer 1993
  • Sommer H, Harrer G. Placebo-controlled double-blind study examining the effectiveness of an Hypericum preparation in 105 patients with depressions. Nervenheilkunde 1993;12:274-7.
Stahl 2002
Sterne 2011
  • Sterne JAC, Egger M, Moher D. Addressing reporting bias. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from, 2011.
Thomson 2007
Urban 2005
  • Urban MO, Ren K, Park KT, Campbell B, Anker N, Stearns B, et al. Comparison of the antinociceptive profiles of gabapentin and 3-methylgabapentin in rat models of acute and persistent pain: implications for mechanism of action. Journal of Pharmacology and Experimental Therapeutics 2005;31:1209-16.
Ursin 1997
Verbeke 2000
  • Verbeke M, Molenberghs G. Linear Mixed Models for Longitudinal Data. New York: Springer, 2000.
Verdu 2008
Verhaak 2006
Ware 1992
Wessely 1999
Whitehead 2002
  • Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?. Gastroenterology 2002;122:1140-56.
Wittchen 1992
  • Wittchen HU, Essau CA, Vonzerssen D, Krieg JC, Zaudig M. Lifetime and 6-month prevalence of mental disorders in the Munich follow-up-study. European Archives of Psychiatry and Clinical Neuroscience 1992;241:247-58.
Wittchen 2005
Wittchen 2011
  • Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B, et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology 2011;21:655-79.
Witthöft 2010
Woelk 2000
World Health Organisation 1975
  • World Health Organisation. International Classification of Diseases. 9th revision (ICD-9). Geneva, Switzerland: World Health Organisation, 1975.
World Health Organisation 1990
  • World Health Organisation. Composite International Diagnostic Interview (CIDI). Geneva, Switzerland: World Health Organisation, 1990.
World Health Organisation 1992
  • World Health Organisation. International Statistical Classification of Diseases. 10th Revision (ICD-10). Geneva, Switzerland: World Health Organisation, 1992.
Yunus 2007